The immune-enhancing effects of selenium (Se) supplementation make it a promising complementary and alternative medicine (CAM) modality for boosting immunity against common colds, influenza, and vaccinations. Se supplementation may also provide an inexpensive and effective means of reversing the declining immunity associated with aging and the immunosuppression associated with cancer, its treatment, and with HIV/AIDS. However, not all types of immune responses are equivalently enhanced by Se supplementation. The reasons for this are unclear due to an inadequate understanding of the mechanisms by which this essential micronutrient affects the immune system. In particular, limited information is available regarding the effects of Se on dendritic cells (DCs) and CD4+ T cells, despite the crucial role that these cells play in initiating and shaping immune responses. The objective of this project is to determine how Se, through the actions of specific selenoproteins, influences the activation, proliferation, and differentiation of CD4+ T cells during different types of immune responses. We plan to test the following specific aims: Specific Aim 1. Determine the effect of increasing levels of dietary Se on the activation, differentiation, and proliferation of CD4+ T cells. Specific Aim 2. Identify specific selenoproteins that regulate the activation of CD4+ T cells. Our experimental design involves feeding mice diets that are low (0.08 ppm), medium (0.25 ppm), or high (1.0 ppm) in Se content. The Se concentrations to be used reflect human diets with Se content at moderately low, adequate, or supplemented levels. For Specific Aim 1, these mice will be used to assess the affects of Se status on the phenotype and function of activated CD4+ T cells. The study design will include experiments using purified CD4+ T cells stimulated with plate-bound anti-CD3/CD28, antigen presentation assays using primary DCs and SMARTA TCR-transgenic CD4+ T cells, and in vivo immunizations with either Th1- or Th2-type antigen challenges. The proliferation and differentiation of the CD4+ T cells will be analyzed using established techniques. For Specific Aim 2, experiments will focus on selenoproteins localized to the ER to determine potential roles of each in Ca++ mobilization and T cell activation. Levels of each resident ER selenoprotein will be reduced by siRNA and the effects on activation of CD4+ T cells will be carried out and the effects of Ca++-dependent cell signaling events determined. This newfound knowledge will have a significant impact on guiding the use of Se-supplementation as a CAM modality for optimizing immune responses. Public Health Relevance: The immune enhancing effects of Se supplementation make it a promising complementary and alternative medicine (CAM) modality for boosting immunity. However, the types of immune responses influenced by Se as well as the mechanisms by which Se affects immune responses are not clear. The goal of this project is to determine the mechanisms by which this potent antioxidant affects the immune system with the intent of providing an important step toward optimal use of Se supplementation.